Abstract
Presentation Description :
Hereditary retinal disease and age related macular degeneration (AMD) are major causes of irreversible blindness in the UK. The lack of effective treatments for these conditions means there is a requirement to develop new therapies. Both conditions involve the loss of the light sensitive cone and rod photoreceptor cells in the retina. Photoreceptor replacement aims to restore vision by the transplantation of healthy cells, ideally derived from a renewable source. Once transplanted, these cells must form new synaptic connections with their target cells, the bipolar cells, within the host retina. Restoring functional connectivity following transplantation is an ambitious goal for CNS repair. Nonetheless, the macula, which is crucial for high acuity daylight vision occupies a small area and relatively few functional photoreceptor cells may be required to achieve useful vision, so even low efficiency cone photoreceptor transplantation may result in clinical benefit. Stem cell biology has seen extraordinary progress in the past decade and we, and others, now have the ability to generate of large numbers of transplantable photoreceptors from a variety of murine and human stem cell sources.
While there are some indications of new connections being formed between transplanted photoreceptors and host bipolar cells, achieving robust functional synaptic connectivity remains a significant challenge, particularly in advanced retinal disease, where the retina can undergo many, often inhibitory, changes. Here, I will describe our recent results examining the ability to rescue visual function following transplantation of human stem cell-derived cone photoreceptors into models of end-stage retinal degeneration. We show that hESC-derived cones survive and mature within the mammalian retina and induce the re-expression of post-synaptic markers in host bipolar cells, which also seek out nascent donor photoreceptor terminals. When present in sufficiently large numbers, hESC-eried cone photoreceptors are capable of driving light-evoked activity in host retinal ganglion cells, as assessed using Multi-Electrode Array recordings. I will also describe progress made towards defining the extent to which such functional rescue is underpinned by the formation of new functional synapses, as assessed using synaptic tracing and recording technqiues.
This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.